Alternative therapeutic approaches for the control of brain inflammation secondary to antihelminthic therapy in neurocysticercosis using a novel experimental pig model

使用新型实验猪模型控制神经囊尾蚴病抗蠕虫治疗继发脑炎症的替代治疗方法

• 批准号: 10581627
• 负责人: Gianfranco Arroyo
• 金额: $ 13.47万
• 依托单位: UNIVERSIDAD PERUANA CAYETANO HEREDIA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-08 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10581627
• 关键词: Acute; Adrenal Cortex Hormones; Albendazole; Animal Model; Animals; Anthelmintics; Anti-Inflammatory Agents; Antiinflammatory Effect; Antimetabolites; Blood brain barrier dysfunction; Brain; Brain Edema; Central Nervous System Cysts; Clinical; Clinical Research; Controlled Study; Cyst; Deterioration; Developed Countries; Dexamethasone; Diagnosis; Dose; Early treatment; Edema; Encephalitis; Etanercept; Evaluation; Family suidae; Genes; Goals; Histologic; Human; Human Pathology; Immigrant; Immune response; Infection; Inflammation; Inflammatory Response; Injections; Intracarotid; Intracranial Hypertension; Larva; Lesion; Life; Local Acute Inflammatory Response Pathway; Methotrexate; Modeling; Neurocysticercosis; Neurons; Outcome Measure; Parasites; Patients; Permeability; Pharmaceutical Preparations; Population; Praziquantel; Process; Recurrence; Regimen; Resolution; Scheme; Secondary to; Seizures; Steroids; Study models; TNF gene; Taenia solium; Testing; Therapeutic; acquired epilepsy; appropriate dose; brain tissue; clinical practice; evidence base; improved; inflammatory marker; mind control; novel; novel therapeutic intervention; porcine model; response; side effect; tool; translational study; tumor necrosis factor-alpha inhibitor

Alternative therapeutic approaches for the control of brain inflammation secondary to antihelminthic therapy in neurocysticercosis using a novel experimental pig model PROJECT SUMMARY Neurocysticercosis (NCC) is the infection of the human brain by the larvae of the pork tapeworm Taenia solium and is a major cause of seizures in most of the world. Antihelminthic therapy induces cyst damage and activates the host immune response, which results in brain inflammation and edema. Corticosteroids are commonly administered concomitant with antihelminthic drugs to control the early treatment-induced inflammatory response. However, an ideal therapeutic scheme using corticosteroids has not been established, corticosteroid therapy is suboptimal in some forms of NCC, and its use may also lead to undesirable side- effects. A better understanding of the immunopathological processes associated with CNS cyst infection and in response to antihelminthic therapy is essential to improve the control of the treatment-induced brain inflammation and to evaluate potential corticosteroid-sparing/replacing agents. The lack of an appropriate animal model for NCC has however, limited our ability to achieve these goals. We recently demonstrated that intra-carotid injection of T. solium activated oncospheres in pigs reproduces CNS cyst infection efficiently, thus providing a suitable animal model for the study of NCC. In this proposal, we will optimize the intra-carotid injection model by determining the number of activated oncospheres required to consistently reproduce NCC in pigs, as well as to characterize the immunopathological processes associated with CNS cyst infection and in response to antihelminthic therapy with albendazole plus praziquantel. Subsequently, we will conduct two trials in pigs with experimental NCC: In the first trial, we will determine the optimal dose of two alternative anti-inflammatory drugs: etanercept (ETN) or methotrexate (MTX) in the control of the brain inflammatory response that results from antihelminthic therapy; the second trial will compare the optimal dose of ETN and MTX versus the wide-spectrum, corticosteroid dexamethasone (DEX) in the control of pericystic brain inflammation after antihelminthic therapy. We expect that our findings will provide the base evidence for translational studies testing ETN or MTX in controlled studies in NCC patients.

控制继发性脑炎症的替代治疗方法 使用新型实验猪模型进行神经囊尾蚴病的抗蠕虫治疗 项目概要 神经囊尾蚴病 (NCC) 是由猪肉绦虫带绦虫幼虫感染人类大脑 钠，是世界大部分地区癫痫发作的主要原因。抗蠕虫治疗会引起囊肿损伤并 激活宿主免疫反应，导致脑部炎症和水肿。皮质类固醇是 通常与抗蠕虫药物同时服用，以控制早期治疗引起的 炎症反应。然而，尚未建立使用皮质类固醇的理想治疗方案， 皮质类固醇治疗在某些形式的 NCC 中效果不佳，并且其使用还可能导致不良副作用 影响。更好地了解与中枢神经系统囊肿感染相关的免疫病理学过程 对抗蠕虫治疗的反应对于改善治疗引起的大脑的控制至关重要 炎症并评估潜在的皮质类固醇节省/替代药物。缺乏合适的 然而，NCC 的动物模型限制了我们实现这些目标的能力。 我们最近证明，颈动脉内注射猪绦虫激活的甲球可以繁殖 CNS囊肿感染有效，从而为NCC的研究提供了合适的动物模型。在这个提案中，我们 将通过确定所需的激活oncospheres的数量来优化颈动脉内注射模型 在猪中一致地重现 NCC，并表征相关的免疫病理过程 患有中枢神经系统囊肿感染以及对阿苯达唑加吡喹酮抗蠕虫治疗有反应。 随后，我们将在患有实验性 NCC 的猪身上进行两项试验：在第一项试验中，我们将确定 两种替代抗炎药的最佳剂量：对照中的依那西普 (ETN) 或甲氨蝶呤 (MTX) 抗蠕虫治疗引起的大脑炎症反应；第二次试验将比较 ETN 和 MTX 与广谱皮质类固醇地塞米松 (DEX) 控制的最佳剂量 抗蠕虫治疗后出现脑囊周炎症。我们希望我们的研究结果能够提供基础 在 NCC 患者的对照研究中测试 ETN 或 MTX 的转化研究的证据。